This project elucidates mechanisms of dilated cardiomyopathy (DCM) in AIDS. Cardiac infection with human immunodeficiency virus-1 (HIV-1), intramyocardial activity of HIV-1 proteins, and toxicity from antiretroviral agents each is postulated to cause AIDS DCM, Experiments in this proposal assess the individual impact of HIV-1 infection, HIV-1 proteins, and anti-AIDS therapeutics on the structure and function of the cardiac myocyte in AIDS DCM. Transgenic mice (TG) serve as key biological tools to explore mechanisms of AIDS DCM. Three TG strategies define 1) effects of targeted myocardial expression of HIV-1 using a replication-incompetent HIV-1 (NL4-3 gag/pol) driven by the cardiac specific alpha myosin heavy chain (alpha-MyHC) promoter; 2) effects of targeted cardiac specific expression of HIV-1 enzymes (e.t. protease) driven by the alpha-MyHC promoter; and 3) systemic events in AIDS DCM using a published TG that expresses replication defective NL4-3 gag/pol systemically. TGs treated with anti-HIV-1 chemotherapy help define structural and functional cardiovascular side effects contributing to AIDS DCM. AIMS address scientific questions about AIDS DCM: AIM 1 (PATHOLOGICAL): to define myocardial structural changes cellularly and subcellularly. Experiments localize and quantitate cardiac and HIV-1 mRNAs and proteins and cardiac mtDNA and mtRNA in TGs with AIDS DCM. Light microscopy, transmission electron microscopy (TEM), immuno-TEM and in situ hybridization localize HIV-1 gene products and pinpoint HIV-1 in cardiac myocyte subcellular compartments. AIM 2 (PHYSIOLOGICAL): to define cardiac performance in AIDS DCM. Isolated cardiac myocytes and work performing heart preparations identify changes in contractility and relaxation in TGs with AIDS DCM. Expression of cardiac Ca transporter proteins and their mRNAs is analyzed in isolated cardiac myocytes. AIM 3 (CELL/MOLECULAR BIOLOGICAL): to define cardiac mtDNA replication, mtRNA abundance, and mitochondrial polypeptide synthesis in AIDS DCM. Southern and Northern analysis respectively define mtDNA and mtRNA abundance in TG hearts. Biosynthetic labeling of polypeptides is determined in isolated mitochondria. Altered expression of mtRNA and mitochondrial proteins reflect altered energy genesis. (End of Abstract)